Dr. Renee Prater has completed her D.V.M., M.S. in physiology, residency in clinical pathology, and is a Ph.D. candidate in toxicology with an expected completion date of 12/2001. She is a highly motivated scientist who sees this award as an opportunity to advance her research career as an independent primary investigator in developmental immunotoxicology. The proposed research will investigate mechanisms by which maternal immune stimulation prevents methylnitrosourea (MNU)-induced birth defects. MNU's teratogenic effects are dose-specific and dependent upon the time of exposure in relation to gestational age. Organ systems affected by MNU include the central nervous, lymphoid, digestive, genitourinary, and limbs. Data from the laboratory have demonstrated that nonspecific activation of the murine maternal immune system can dramatically reduce several chemical-induced birth defects, including MNU-induced digital defects (DDs), and that maternal immune stimulation normalizes teratogen-altered expression of fetal regulatory genes in palatal development. Other investigators have reported that altered gene expression in MNU-induced teratogenesis can be normalized with dietary antioxidant supplementation (Hulten et al. 1998). A focused examination of altered gene expression and protection from MNU-induced DD is now logical. Specifically, the following hypotheses will be tested: 1) MNU affects gene expression regulating digital development; 2) maternal immune stimulation normalizes gene expression through regulatory proteins secreted by activated immune cells, and 3) protection from MNU-induced digital defects can also result from dietary supplementation with the antioxidant butylated hydroxytoluene (BHT) in a process involving similar effects on regulatory genes. These studies are expected to significantly increase our understanding of genetic mechanisms by which maternal immune modulation reduces this specific birth defect. Clearly, this research is of importance to human health, as determining the mechanisms will improve the understanding of this disorder and contribute to means for prevention or cure. This research under the guidance of Drs. Steven Holladay and Eric Wong at Virginia Tech.